1. Field of the Invention
The present invention relates generally to the fields of organic chemistry and immunology. More specifically, the present invention relates to derivatives of butyric acid and their use a s inactivators of antigen-specific T cells.
2. Description of the Related Art
Helper T cells (Th) are regulatory lymphocytes which cooperate with other lymphocytes to expedite an immune response. Generally, helper T cells recognize protein antigens after the antigens have been processed into peptide fragments and have become associated with a class II MHC molecules. Autoimmunity is an immune response directed against self-antigens resulting from the breakdown of the normal mechanisms of self-tolerance that prevent the production of functional self-reactive clones of T cells.
Butyric acid is a naturally occurring four carbon fatty acid found in the gut as a result of fiber fermentation. n-Butyrate is well known as an anti-neoplastic agent and for its ability to induce G1 arrest in virtually all cell types tested and to induce cytodifferentiation of many different transformed cell lines. In murine CD4+T cells of the T helper type 1 (Th1), anergy is induced when the cells are pretreated with n-butyrate and antigen thereby becoming unresponsive; i.e., they exhibit a long lasting inability to proliferate or secrete cytokines, to a subsequent stimulation with antigen in secondary cultures (Gilbert and Weigle, J. of Immunology 151(3) 1245-1254 (1993)). In contrast, Th1 cells treated with n-butyrate alone, in the absence of antigen stimulation, are totally unaffected by the drug.
Th1 cells exposed to n-butyrate in the presence of antigen lose their ability to proliferate to antigen, but retain their ability to proliferate in cultures stimulated with exogenous Interleukin-2 (IL-2). Therefore, Th1 cell unresponsiveness after exposure to n-butyrate is not caused merely by drug toxicity. Similarly, the inhibitory effects of n-butyrate are not caused by a drug-induced shift in Th1 cell proliferation kinetics. The induction of tolerance with n-butyrate is antigen-dependent, and is linked to a decrease in antigen-induced secretion of IL-2.
The immunotherapeutic potential for n-buytyrate is limited by its short half-life in vivo (3-6 minutes) (Daniel et al., 1989). Even when it is administered by intravenous infusion, n-butyrate is found to be clinically ineffective as an anti-cancer agent (Miller et al., 1987; Novogrodsky et al., 1983). As n-butyrate contains sodium and as it has a half-life of six minutes, large doses are required resulting in a high dose of sodium administered to a patient.
n-Butyrate/tributyrin derivatives with ester and amide functional groups undergo hydrolysis in vivo to release butyrate. This leads to a more sustained release of butyric acid and significantly prolongs the duration of action. These butyrate derivatives also contain an ionizable amino group. This not only allows the compound to be converted to water soluble salts (e.g. hydrochloride), but also avoids the necessity of using the sodium salt of butyric acid which could lead to sodium overload. Therefore, when administered briefly during a n autoimmune response, a member of the butyrate/tributyrin family of drugs acts to convert activated self-reactive T cells to an unresponsive state, but has no effect on the majority of resting T cells.
The prior art is deficient in effective means of using butyrate/tributyrin prodrugs to convert activated self-reactive T-cells during an autoimmune response to an unresponsive state without adversely effecting the majority of resting T cells. The present invention fulfills this long-standing need and desire in the art.
In one embodiment of the present invention, there are provided a series of compounds having structural formulas 
wherein n1 is 1 to 5, n2 is 1 to 4 and m is 1 to 3; X is O or NH; Y is CH2, O, S, NH, NR; wherein R is selected from the group consisting of a straight-chain aliphatic group, a branched-chain aliphatic group and an alicyclic group; wherein Rxe2x80x2 is selected from the group consisting of hydrogen, methyl and ethyl; wherein when Y is O, n1 can not be 1; and wherein X and Rxe2x80x2 are independently optionally substituted at C2, C3 or C4 in compounds of Fomula IV or a pharmaceutically acceptable salt thereof.
In another embodiment of the present invention, there is provided a pharmaceutical composition, comprising a compound of the present invention and a pharmaceutically acceptable carrier.
In yet another embodiment of the present invention, there is provided a method of inactivating antigen-specific T cells in an individual in need of such treatment, comprising the step of administering to said individual an effective amount of compound having the structure 
wherein n1 is 1 to 5, n2 is 1 to 4 and m is 1 to 3; X is O or NH; Y is CH2, O, S, NH, NR; wherein R is selected from the group consisting a straight-chain aliphatic group, a branched-chain aliphatic group and an alicyclic group; wherein Rxe2x80x2 is selected from the group consisting of hydrogen, methyl and ethyl; and wherein X and Rxe2x80x2 are independently optionally substituted at C2, C3 or C4 in compounds of Fomula IV or a pharmaceutically acceptable salt thereof.
Other and further aspects, features, benefits, and advantages of the present invention will be apparent from the following description of the presently preferred embodiments of the invention given for the purpose of disclosure.